Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C‑Domain: Implications for Drug Design

Omapatrilat
was designed as a vasopeptidase inhibitor with dual
activity against the zinc metallopeptidases angiotensin-1 converting
enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic
domains (nACE and cACE), which exhibit different substrate specificities.
Here, we report high-resolution crystal structures of omapatrilat
in complex with nACE and cACE and show omapatrilat has subnanomolar
affinity for both domains. The structures show nearly identical binding
interactions for omapatrilat in each domain, explaining the lack of
domain selectivity. The cACE complex structure revealed an omapatrilat
dimer occupying the cavity beyond the S2 subsite, and this
dimer had low micromolar inhibition of nACE and cACE. These results
highlight residues beyond the S2 subsite that could be
exploited for domain selective inhibition. In addition, it suggests
the possibility of either domain specific allosteric inhibitors that
bind exclusively to the nonprime cavity or the potential for targeting
specific substrates rather than completely inhibiting the enzyme.